tbuckley/cabot-search huggingface dataset:
MicroRNAs as therapeutic targets in cardiovascular disease
Authors: Bernhard Laggerbauer, Stefan Engelhardt
Journal: Journal of Clinical Investigation (2022)

The discovery of microRNAs and their role in diseases was a breakthrough that inspired research into microRNAs as drug targets. Cardiovascular diseases are an area in which limitations of conventional pharmacotherapy are highly apparent and where microRNA-based drugs have appreciably progressed into preclinical and clinical testing. In this Review, we summarize the current state of microRNAs as therapeutic targets in the cardiovascular system. We report recent advances in the identification and characterization of microRNAs, their manipulation and clinical translation, and discuss challenges and perspectives toward clinical application.
Determinants of overall survival (OS) of primary plasma cell leukemia (pPCL): A National Cancer Database (NCDB) analysis of years 2004 to 2009.
Authors: Kevin Scott Landau, Kelsey Lynn Mowery, Hong Liang, Chieh Lin Fu, Chakra Pani Chaulagain
Journal: Journal of Clinical Oncology (2022)

8066 Background: Outcome data for pPCL is limited due to the rare &amp; aggressive nature of the disease. In this retrospective analysis, we utilized NCDB to identify factors contributing to 1 &amp; 5-year OS of pPCL patients treated at CoC-accredited facilities across USA. Methods: Using the NCDB, we identified N= 325 pPCL patients diagnosed between 2004-2009 after excluding entries missing relevant values. Univariate analysis was used to summarize &amp; assess the potential survival factors individually &amp; multivariate Cox regression analysis with backward elimination (using significance level of p&lt;0.05) was utilized to identify the independent survival factors. Kaplan-Meier (KM) survival curves of patient cohort were also produced. SAS version 9.4 was used to analyze the data. Results: Multivariate Cox regression analysis with backward elimination method revealed that there were 4 significant independent survival factors including sex, Charlson-Deyo Comorbidity Index (CCI), facility type, and insurance, while age &amp; year-of-diagnosis were not independent survival factors (Table). Male patients were more likely to die compared to female patients (HR=1.40, p=0.005); patients with CCI ≥1 had higher chance to suffer death compared to patients with CCI= 0 (HR=1.52, p=0.002); patients not treated at an academic center (AC) had lower survival compared to those treated at ACs (HR=1.35, p=0.001); and patients without private insurance (PI) were more likely to suffer death compared to those with PI (HR=1.54, p=0.001). The 1 &amp; 5-year survival rates for whole cohort were 51.3% (95%CI: 45.8%-56.8%), and 18.9% (95%CI: 14.6%-23.2%) using KM estimate, respectively. Only 6/325 =1.8% patients underwent autologous hematopoietic stem cell transplant (HSCT). Detailed analysis will be presented. Conclusions: In this large analysis of pPCL patients, we identified that being female, having less comorbidities, getting treatment at ACs, and having PI had significantly greater OS. Overall, pPCL is associated with low survival rates both at 1 &amp; 5-years and HSCT may be enormously under-utilized for pPCL patients in the real world setting. [Table: see text]
Cross-ancestry polygenic risk score for breast cancer risk assessment.
Authors: Placede Tshiaba, Jiayi Sun, Dariusz Ratman, Tate Tunstall, Brynn Levy, Premal Shah, Matthew Rabinowitz, Akash Kumar, Kate Im
Journal: Journal of Clinical Oncology (2022)

10540 Background: Breast cancer (BC) risk is influenced by many common variants with small effects. Polygenic risk scores (PRS) weight these variants based on genome-wide association studies (GWAS) and aggregate them into a single measure. PRS has primarily shown benefit in Caucasian women. We established a cross-ancestry polygenic model (caPRS) which assesses risk of breast cancer across multiple ancestries. Methods: Performance of multiple BC polygenic models, both published and developed in-house, were evaluated for each of five ancestry groups: European, African, South Asian, East Asian, and Admixed American. To account for ancestry-specific mean and variance, we computed principal components (PCs) for all women by projecting their genotypes onto PCs calculated on individuals in the 1000 Genomes Project (1KGP). We next centered each ancestry-specific PRS by subtracting the PRS predicted from a linear regression of PRS against the first four PCs in unaffected individuals. Each centered PRS was then divided by the SD of the corresponding 1KGP population. We defined a cross-ancestry polygenic model as a linear combination of the best performing PRS model for each ancestry group weighted by fractional ancestry. Association of the caPRS with breast cancer risk was tested in a validation cohort of &gt;130,000 women consisting of multiple independent cohorts (the Women’s Health Initiative, the Multiethnic Cohort, the ROOT cohort and the UK Biobank) using a multivariate logistic regression model that included caPRS, age, self-reported ancestry, personal history of ovarian cancer (when available) and first-degree family history of BC. Discrimination was assessed by the odds ratio (OR) per SD and the area under the receiver-operator curve (AUC). Results: This study included women with African/Black, East Asian, Caucasian/White, Hispanic/Latino, South Asian and ‘Other’ self-reported ancestry. The ancestry-specific models included in the caPRS ranged in size from 173 to &gt;800,000 variants. The caPRS was associated with BC risk for women in each self-reported ancestry (Table). The caPRS offered a modest increase in performance over a commonly implemented 313-SNP PRS in non-European ancestries, most significantly in African/Black women where the OR per SD increased from 1.24 (1.08 - 1.43), p-value 2.3x10-3. Conclusions: The caPRS performed well for women of any ancestry and allows flexibility to update ancestry-specific models. These results suggest the caPRS has the potential to improve the clinical utility of existing clinical risk predictors. [Table: see text]
Intravesical therapy with the trifunctional anti-EpCAM/CD3 bsAb Catumaxomab is well tolerated and shows encouraging preliminary efficacy in patients with high-risk NMIBC (CATUNIBLA phase I trial).
Authors: Felix Albert, Aleksander Antoniewicz, Tobias Grantzow, Guenter Fingerle-Rowson, Peter Ruf, Horst Lindhofer, Maximilian Kriegmair, Ralph Oberneder
Journal: Journal of Clinical Oncology (2022)

e16555 Background: Tx of high-risk NMIBC is challenging due to a high risk of recurrence. Novel therapeutic options are highly anticipated to avoid cystectomy and disease progression. Malignant transitional cells express EpCAM. The trifunctional anti-EpCAM/CD3 bsAb Catumaxomab (CAT) mediates cell killing against human BC. This dose escalating Phase I trial (NCT04819399) investigates the safety of intravesical CAT in high-risk NMIBC. Methods: Following first TUR-B, pts with newly diagnosed high-risk NMIBC were enrolled and received 6 x weekly intravesical CAT instillations, each of 2h duration) at a dose of 50 or 70μg. Subsequently, 2 nd TUR-B and adjuvant instillation therapy (tx) was performed as SoC. Here, we report the safety and preliminary efficacy of dose cohorts 1 and 2. Results: 7 Pts are included, 5 with pTa, 2 with pT1 disease. There were 5 concomitant pTis. 6/7 pts received the planned 6 x weekly CAT instillations. 1 pt discontinued after 1 instillation due to recurrent UTI. No DLTs occurred. 28 AEs were observed in 6/7 pts, all of gr 1-2 except two unrelated gr 3 AEs . 2/7 pts had an unrelated SAE each (1 hydronephrosis, 1 recurrent fever after BCG). For 6/7 pts cytokines were below LLQ. In one pt of cohort 2 low amounts of IL-6 and IL-8 were detectable. Weak HAMA responses in 5/6 pts transiently occurred at days 29 and 43. CAT instillations led to transient increases of urinary leukocytes. During and after CAT treatment, there was a strong trend towards reduction of EpCAM+ cells in urine. At 2 nd TUR-B tumour persistency was observed in two patients only. Remarkably, 3/5 pTis were no longer detected at 2 nd TUR-B. So far, 5/7 pts received adjuvant BCG, 2 pts declined. 7/7 pts achieved CR as best response. While 2/3 pts in the 50 μg cohort had a recurrence, no recurrence was observed in the 70 μg cohort. Conclusions: Intravesical instillations with the trifunctional, anti-EpCAM/anti-CD3 bsAb Catumaxomab are well tolerated in pts with high risk NMIBC. CAT does not enter systemic circulation and elicits only low and transient immunogenicity. The MTD is not reached and dose escalation is still ongoing with cohort 3 (100 μg)(updated results will be presented at meeting). The reduction in EpCAM+ urine cells indicates potential activity of this novel immunotherapy and the high CR rate of Tis at the end of CAT therapy is promising. Clinical trial information: NCT04819399. [Table: see text]
Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma
Authors: Michael L Wang, Wojciech Jurczak, Mats Jerkeman, Judith Trotman, Pier L Zinzani, David Belada, Carola Boccomini, Ian W Flinn, Pratyush Giri, Andre Goy, Paul A Hamlin, Olivier Hermine, José-Ángel Hernández-Rivas, Xiaonan Hong, Seok Jin Kim, David Lewis, Yuko Mishima, Muhit Özcan, Guilherme F Perini, Christopher Pocock, Yuqin Song, Stephen E Spurgeon, John M Storring, Jan Walewski, Jun Zhu, Rui Qin, Todd Henninger, Sanjay Deshpande, Angela Howes, Steven Le Gouill, Martin Dreyling
Journal: New England Journal of Medicine (2022)

Ibrutinib, a Bruton's tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma.
Management of urolithiasis in patients with renal anomaly: Multicenter KSER research series
Authors: W.B. Kim, K. Choi, K.H. Shim, S.W. Yang, D.K. Kim, M.S. Choo, D.Y. Chung, H.D. Jung, S.W. Lee, S. Paick, S.H. Jeon, J.Y. Lee
Journal: European Urology (2022)
BCL6-dependent TCF-1+ progenitor cells maintain effector and helper CD4+ T cell responses to persistent antigen
Authors: Yu Xia, Katalin Sandor, Joy A. Pai, Bence Daniel, Saravanan Raju, Renee Wu, Sunnie Hsiung, Yanyan Qi, Tenzin Yangdon, Mariko Okamoto, Chun Chou, Kamir J. Hiam-Galvez, Robert D. Schreiber, Kenneth M. Murphy, Ansuman T. Satpathy, Takeshi Egawa
Journal: Immunity (2022)
Can ablation therapy be an alternative treatment to partial nephrectomy for clinical T1b renal tumors?: A systematic review and meta-analysis
Authors: T. Yanagiswawa, K. Mori, T. Kawada, R. Sari Motlagh, H. Mostafaei, F. Quhal, E. Laukhtina, P. Rajwa, F. König, M. Pallauf, B. Pradere, J. Miki, T. Kimura, S. Egawa, S.F. Shariat
Journal: European Urology (2022)
LGG-08. MR Imaging of pediatric low-grade gliomas: Pretherapeutic differentiation of<i>BRAF</i> V600E mutation,<i>BRAF</i>-Fused and Wild-Type tumors in patients without Neurofibromatosis-1
Authors: Andrew Trasolini, Craig Erker, Sylvia Cheng, Cameron Crowell, Kathryn McFadden, Rahim Moineddin, Michael Sargent, Daddy Mata-Mbemba
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE: The prognosis and treatment of pediatric low-grade gliomas (pLGGs) is influenced by their molecular subtype. MRI remains the mainstay for initial work-up and surgical planning. We aimed to determine the relationship between imaging patterns and molecular subtypes of pLGGs. METHODS: This is a bi-institutional retrospective study for patients diagnosed from 2004 to 2021 with pathologically confirmed pLGG, molecularly defined as BRAF fusion (KIAA1549-BRAF), BRAF V600E mutation, or wild-type (negative for both BRAF V600E mutation and BRAF fusion). Two neuroradiologists, blinded, independently reviewed imaging parameters on the initial MRI and discrepancies were solved by consensus. Bivariate analysis was used followed by pairwise comparison of Dwass, Steel, and Critchlow-Fligner methods to compare the 3 molecular subtypes. Agreement between reviewers was assessed using Kappa (k). RESULTS: 70 patients were included: 30 with BRAF fusion, 19 with BRAF V600E mutation, and 21 wild-type. There was substantial agreement between the two readers for overall imaging variables (k=0.75). BRAF fusion tumors compared to V600E and wild-type had larger size (p=0.0022), greater mass effect (p=0.0053), and increased rate of hydrocephalus (p=0.0002). BRAF fusion tumors had increased frequency of diffuse enhancement compared with BRAF V600E and wild-type (p &amp;lt;0.0001). BRAF V600E mutant tumors were more often located in a cerebral hemisphere (p &amp;lt;0.0001). Diffusion restriction (qualitatively) was uncommon but only seen in BRAF V600E (p=0.0042) with lower ADC ratio (quantitatively) (p=0.003). Additionally, BRAF V600E mutant tumors appeared more infiltrative than BRAF fusion and wild-type (p=0.0002). CONCLUSION:BRAF fusion and BRAF V600E mutant pLGG have unique imaging features that can be used to differentiate from each other and wild-type pLGG using standard radiology review with high inter-reader agreement. In the era of targeted therapy, these features can be useful for therapeutic planning prior to surgery.
The effects of bone targeted therapy in patients with greater than two years survival with metastatic breast cancer and bone metastasis.
Authors: Athira Jayan, Akshara Singareeka Raghavendra, Roland L. Bassett, Carlos Hernando Barcenas
Journal: Journal of Clinical Oncology (2022)

e13076 Background: Administration of bone targeted therapy such as zoledronic acid (ZA) or of denosumab (D) decrease the risk of skeletal related events (SRE) such as radiation to the bone, pathological bone fractures, and spinal cord compression in patients with a diagnosis of metastatic breast cancer (MBC) and bone metastasis. As these patients continue to live longer it is unknown what are the impacts from long-term administration of ZA or D among those who live longer than 2 years. Methods: This was a retrospective analysis of patients with MBC and bone metastasis who lived for more than 2 years since diagnosis and received treatment at MD Anderson Cancer Center for MBC in addition to ZA and/or D between 2015 and 2021. Patient demographics, date of diagnosis, tumor characteristics, bone targeted agent treatment plans and SRE were extracted from the institutional database and electronic health records. We defined 3 patterns of receipt of bone targeted therapy: Pattern A: ZA every 3-4 weeks; Pattern B: D every 4-6 weeks; Pattern C; D every 4-6 weeks for a period followed by every 3 months. The association between these patterns and SRE was assessed using Fisher’s exact test. Results: We included 178 patients: Pattern A with 49 patients, Pattern B with 85 patients, and Pattern C with 44 patients. The proportion of patients who suffered a SRE in Patterns A, B, and C were 22.4% (11/49), 20% (17/85), and 21.4% (10/44). There was no statistical difference in the proportion of SRE between these three groups (p = 0.92). Conclusions: We did not observe a difference in the rate of SRE between the three different patterns of bone targeted therapy administration in patients with MBC and bone metastasis. Other treatment patterns will be considered in future analysis.[Table: see text]
ASPEN: Long-term follow-up results of a phase 3 randomized trial of zanubrutinib (ZANU) versus ibrutinib (IBR) in patients with Waldenström macroglobulinemia (WM).
Authors: Constantine Si Lun Tam, Ramón Garcia-Sanz, Stephen Opat, Shirley D'Sa, Wojciech Jurczak, Hui-Peng Lee, Gavin Cull, Roger G. Owen, Paula Marlton, Bjorn E. Wahlin, Alessandra Tedeschi, Jorge J. Castillo, Tanya Siddiqi, Christian Buske, Veronique Leblond, Wai Y. Chan, Jingjing Schneider, Aileen Cohen, Jane Huang, Meletios A. Dimopoulos
Journal: Journal of Clinical Oncology (2022)

7521 Background: ASPEN is a randomized, open-label, phase 3 study comparing ZANU, a potent and selective Bruton tyrosine kinase inhibitor (BTKi), with the first-generation BTKi IBR in patients with WM. We present data with a median follow-up of 43 months. Methods: Patients with MYD88 mutations were assigned to cohort 1 and randomized 1:1 to receive ZANU 160 mg twice daily or IBR 420 mg once daily. Randomization was stratified by CXCR4 mutational status and lines of prior therapy (0 vs 1-3 vs &gt; 3). Patients without MYD88 mutations were assigned to cohort 2 and received ZANU 160 mg twice daily. The primary endpoint was proportion of patients achieving complete response or very good partial response (CR+VGPR). Results: A total of 201 patients (ZANU arm, n = 102; IBR arm, n = 99) were enrolled in cohort 1 and 28 patients were enrolled in cohort 2. A larger proportion of patients in the ZANU arm of cohort 1 vs IBR had CXCR4 mutations by next-generation sequencing (32% vs 20%, or 33 of 98 vs 20 of 92 with data available) and were aged &gt; 75 years (33% vs 22%). Median duration of treatment was 42 months (ZANU) and 41 months (IBR), with 67% and 58% remaining on treatment, respectively. The CR+VGPR rate by investigator was 36% with ZANU vs 22% with IBR ( p= 0.02) in cohort 1, and 31% in cohort 2. One patient achieved CR (cohort 2). In patients with wild type or mutant CXCR4 from cohort 1, CR+VGPR rates with ZANU vs IBR were 45% vs 28% ( p= 0.04) and 21% vs 5% ( p= 0.15) , respectively. Median progression-free survival and overall survival were not yet reached. Rates of atrial fibrillation, diarrhea, hypertension, localized infection, hemorrhage, muscle spasms, pneumonia, and adverse events leading to discontinuation or death were lower with ZANU vs IBR (Table). Exposure-adjusted incidence rates of atrial fibrillation/flutter and hypertension were lower with ZANU vs IBR (0.2 vs 0.8 and 0.5 vs 1.0 persons per 100 person-months, respectively; p&lt; 0.05). Rate of neutropenia was higher and rate of grade ≥3 infection was lower with ZANU vs IBR. Safety outcomes of ZANU were similar between cohorts 1 and 2. Conclusions: ASPEN is the largest phase 3 trial with head-to-head BTKi comparison in WM. At a median follow-up of 43 months, ZANU was associated with higher CR+VGPR rate and demonstrated clinically meaningful advantages in long-term safety and tolerability vs IBR. Clinical trial information: NCT03053440. [Table: see text]
Use of Race in Pediatric Clinical Practice Guidelines
Authors: Courtney A. Gilliam, Edwin G. Lindo, Shannon Cannon, L’Oreal Kennedy, Teresa E. Jewell, Joel S. Tieder
Journal: JAMA Pediatrics (2022)

<h3>Importance</h3> National clinical practice guidelines (CPGs) guide medical practice. The use of race in CPGs has the potential to positively or negatively affect structural racism and health inequities. <h3>Objective</h3> To review the use of race in published pediatric CPGs. <h3>Evidence Review</h3> A literature search of PubMed, Medscape, Emergency Care Research Institute Guidelines Trust, and MetaLib.gov was performed for English-language clinical guidelines addressing patients younger than 19 years of age from January 1, 2016, to April 30, 2021. The study team systematically identified and evaluated all articles that used race and ethnicity terms and then used a critical race theory framework to classify each use according to the potential to either positively or negatively affect structural racism and racial inequities in health care. <h3>Findings</h3> Of 414 identified pediatric clinical practice guidelines, 126 (30%) met criteria for full review because of the use of race or ethnicity terms and 288 (70%) did not use race or ethnicity terms. The use of a race term occurred 175 times in either background, clinical recommendations, or future directions. A use of race with a potential negative effect occurred 87 times (49.7%) across 73 CPGs and a positive effect 50 times (28.6%) across 45 CPGs. <h3>Conclusions and Relevance</h3> In this systematic review of US-based pediatric CPGs, race was frequently used in ways that could negatively affect health care inequities. Many opportunities exist for national medical organizations to improve the use of race in CPGs to positively affect health care, particularly for racial and ethnic minoritized communities.
Exploration of Clinician Perspectives on Multidisciplinary Tumor Board Function Beyond Clinical Decision-making
Authors: Bonnie O. Wong, Jacob A. Blythe, Adela Wu, Jason N. Batten, Kristin M. Kennedy, Amanda S. Kouaho, Sherry M. Wren
Journal: JAMA Oncology (2022)

This qualitative study uses interview data to explore clinician perspectives on the function of multidisciplinary tumor boards beyond clinical decision-making.
Assessing surrogacy using restricted mean survival time ratio for overall survival in liver cancer immunotherapy studies.
Authors: Herbert Pang, Tiffany H Leung, James C. M. Ho, Wendy WT Lam, Xiaofei F. Wang
Journal: Journal of Clinical Oncology (2022)

e16222 Background: Recently, immunotherapy has played a crucial role in treating liver cancer, one of the major cancers that contributes to global cancer burden. Overall survival (OS) is widely applied in cancer trials to evaluate the treatment effects of new therapies. However, it requires more patients and longer follow-up time comparing with progression-free survival (PFS). In addition, while assessing the treatment effects of cancer immunotherapy, proportional hazard (PH) assumption is often violated due to issues such as delayed treatment effects. Restricted Mean Survival Time (RMST) ratio is increasingly used for treatment effect evaluation when the PH assumption is violated. Such change prompts an important question whether the surrogacy value of PFS will be affected when RMST ratio is used to characterize treatment effect. The aim of this study is to examine the feasibility of using PFS as a surrogate endpoint for OS when the treatment effect is measured using hazard ratio (HR) versus RMST ratio. Methods: The surrogacy of PFS on OS was evaluated through examining the association between PFS and OS using HR and RMST ratio. Seven immunotherapy studies published between 2000 and 2021 were included (Table). Information of examined studies such as treatment arms information, OS and PFS were collected. RMST ratio for PFS and OS were calculated based on the Kaplan-Meier plots extracted from each article using WebPlotDigitizer 4.4. The weighted least square regression lines and R^2 between OS and PFS for HR and RMST ratio were calculated. Results: Among 7 immunotherapy studies, 4 gave placebos to the control arms as treatments. 2 provided Sorafenib and 1 assigned the same drug as treatment arm but with different schedule. All 7 studies had OS and PFS as the endpoints. 2 studies violated the PH assumptions. Based on the data extracted from examined articles, a moderate correlation (0.52) between PFS and OS was observed for HR while low correlation (0.10) was observed for RMST ratio. Conclusions: The R^2 values differ greatly depending on whether HR or RMST ratio was used for assessing surrogacy. Our finding may have important implications for the design of future immunotherapy liver cancer trials. For future work, increasing the number of included studies for a more comprehensive analysis is needed. Moreover, trial-level surrogacy analysis should be conducted to complement the study-level investigation.[Table: see text]
Nano co-delivery of Plumbagin and Dihydrotanshinone I reverses immunosuppressive TME of liver cancer
Authors: Shulan Han, Shengnan Bi, Tingting Guo, Dandan Sun, Yifang Zou, Lingzhi Wang, Liu Song, Di Chu, Anqi Liao, Xiaohuan Song, Zhuo Yu, Jianfeng Guo
Journal: Journal of Controlled Release (2022)
Covid-19: Suicide rates fell during Brazil’s first wave but increased in older people
Authors: Luke Taylor
Journal: BMJ (2022)

Covid-19: Suicide rates fell during Brazil's first wave but increased in older people Luke TaylorThe number of people who died by suicide in Brazil in 2020 declined overall despite the country being one of the worst affected in the world by the covid-19 pandemic, a study by the country's leading public health institute has found.